Daughter of Anna von Miltitz and Hans von der Saale, she met the married Landgrave Philip at the age of seventeen. Philip wished to marry Saale morganatically rather than keep her as a mistress, as adultery would blacken his religious reputation, but he did not wish to divorce his consort, Christine of Saxony, as he believed that a divorce was equally sinful. On 10 December 1539, he received support from Martin Luther, with the argument that of two evil things, bigamy was better than divorce. The bigamous wedding ceremony took place on 4 March 1540 in Rotenburg Castle in the presence of Martin Bucer and Philipp Melanchthon. Saale never attended court but resided in a house beside the square in Spangenberg.

The bigamy between Margarethe and Philip had a negative effect upon the reformation.